Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Abstract

The NMDA antagonist, memantine (Namenda), and the cholinesterase inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20 mg/kg ip), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5 to 10mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process.

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

“…We observed no neuronal vacuolization or other histopathological changes in the hippocampus, posterior cingulate and retrosplenial cortices at the light microscopy level after memantine administration as previously reported after the administration of NMDA antagonists (Fix et al, 1993(Fix et al, , 1994Creeley et al, 2008). However, our observation that chronic memantine administration was associated with axonal degeneration in the hippocampus may relate to other reported neurotoxic effects of NMDA antagonists (eg PCP, MK-801) (Low and Roland, 2004).…”

“…The selected coronal sections were cut at the level of the decussation of the corpus callosum (approximately À5.30 to À5.60 mm caudal to bregma) to ensure sampling each brain at the same rostrocaudal level. Also, the brain regions selected using this sampling scheme have been reported to be particularly vulnerable to vacuolization induced by the administration of NMDA antagonists (Fix et al, 1993(Fix et al, , 1994Creeley et al, 2008). A total of 10 neurons in each section of the posterior cingulate and retrosplenial cortices and the hippocampus were detected (under  100 objective lens) and evaluated for the presence and severity of interacytoplasmic vacuoles and other features of neuronal damage.…”

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

“…These dosages are close to the lower levels of AChE inhibitor concentrations used in common adult rat models of neuronal damage [32,33,34] and the present data are not intended to demonstrate the evidence of an effective dose.…”

Amyloidosis and Neurodegenerative Diseases: Current Treatments and New Pharmacological Options

“…The first consists in inhibiting the stimulation of NMDA receptors; memantine, riluzole, and D -cycloserine (a partial agonist) inhibit these receptors. However, the combination of memantine with donepezil may be avoided as the second potentiates the toxic effect of the first [48] . The second possibility consists in activating ␣ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with ampakines or with nootropic drugs such as propiracetam, oxiracetam, or aniracetam.…”